Sepsis is an important, life-threatening disease whose incidence is rising. In the United States, it accounts for more than 200,000 deaths and over $16.7billion in health care expenditures. Treatment of this lethal disorder is supportive because the underlying pathophysiology is poorly understood. The normal natural history of epsis has been well-defined. It presents with a hypermetabolic, hyperinflammatory state. Fortunately, clinicians have become quite adept at managing this phase of the syndrome so death early on is rare. Over time, the patient's condition evolves to a state of reduced organ function, the Multiple Organ Dysfunction Syndrome (MODS). Most sepsis-associated deaths occur in patients with MODS and often reflect decreased immune system function. Immune dysfunction may occur because immune cells cease to function or change their pattern of function. If immune dysfunction represents one component of MODS, it is logical to assume that similar changes - either decreased or altered function - occur in other organs. In our studies, weexamine this possibility in liver cells, or hepatocytes. Using a mouse model of sepsis, we have shown that hepatocyte function changes dramatically over time and in the face of severe, as opposed to mild, sepsis. The nature of this change is unknown and therefore therapeutic approaches are lacking. We propose that the change results from an alteration in the pathways by which hepatocytes respond to signals that arise outside anindividual cell. These signals may be initiated by others liver cells, cells in the blood stream or molecules dissolved in the blood. The underlying defect may result from a failure of cells to generate energy for biochemical reactions. We will examine the response to a single mediator, EL-6, and determined if the IL-6signaling pathway is impaired in sepsis. We also will investigate the effects of sepsis on a key enzyme that is responsible for generating energy in liver cells. Finally, we will determine if EL-6administration can reverse the defect. These studies should provide important information regarding septic biology and suggest novel therapeutic approaches.